Pivaloyl chloride → (s)-2-(2-Amino-propionylamino)-5-[3-(2-methoxy-phenyl)-1h-pyrrolo[2,3-b]pyridin-5-yl]-n,n-dimethyl-benzamide hydrochloride

Participants

Reaction Conditions

Reaction Steps

Into a Scintillation vial were added BOC-Ala-OH (50.8 mg, 0.268 mmol), iPr2NEt (50 μL, 0.41 mmol) and methylene chloride. The solution was cooled in an ice-water bath for 3 min, then trimethylacetyl chloride (33 μL, 0.40 mmol) was added. The solution was stirred at 0° C. for 45 min then 2-amino-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-benzamide (96.9 mg, 0.179 mmol) was added, the ice-bath was removed, and the solution was stirred at rt for 2 d. The reaction mixture was concentrated then re-dissolved in MeOH (I mL), and cooled to 0° C. and treated with 50 μL 50% (w/w) aqueous KOH for 30 min or until Ts-removal was complete. The reaction was quenched by addition of 500 μL glacial acetic acid and then concentrated in vacuo. The crude residue was dissolved in EtOAc and filtered (to remove KOAc), then purified by flash column chromatography on SiO2 gel eluting with a 0 to 100 [(10% MeOH in EtOAc):hexanes] gradient. The purified BOC-protected compound was then dissolved in 1 mL methanol and treated with 4M HCl/1,4-dioxane solution (2 mL) for 2.5 h. Lyophilization afforded 149.2 mg of the title compound as a yellow powder. 1H-NMR (500 MHz, d6-DMSO) δ 12.01 (br.s, 1H), 10.16 (br.s, 1H), 8.57 (d, J=2.0 Hz, 1H), 8.26 (app.d, 2H), 8.21 (d, J=2.0 Hz, 1H), 7.80 (dd, J=2, 8 Hz, 1H), 7.74 (d, J=2.5 Hz, 1H), 7.65 (d, J=2.5 Hz, 1H), 7.60 (dd, J=1.5, 7.5 Hz, 1H), 7.55 (d, J=8.5 Hz, 1H), 7.27 (t, J=7 Hz, 1H), 7.11 (d, 8.0 Hz, 1H), 7.04 (t, J=6 Hz, 1H), 4.05 (m, 1H), 3.80 (s, 3H), 2.97, 2.85 (br.s, 6H), 1.41 (d, J=7 Hz, 3H); MS: m/z 558.2 [M+H+].

Provenance & Evidence